Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and is often diagnosed at an advanced stage. We have investigated alpha-fetoprotein (AFP) as a tumor-associated antigen for HCC. We identified major histocompatibility complex class I-restricted peptide epitopes derived from AFP and studied CD8 T-cell responses in vivo and in vitro in ongoing immunotherapy studies. Helper T cells are of critical importance in shaping the immune response; therefore, we investigated the frequency and function of AFP-specific CD4 T cells in the general population and among HCC patients. CD4 T-cell responses were assessed by direct ex vivo multicytokine enzyme-linked immunospot assay and by measurement of cytokine levels using a multicytokine assay. Our analysis indicates that healthy donors have very low frequencies of AFP-specific CD4 T-cell responses, which are of TH1 type, detectable ex vivo. In contrast, these T cells were either reduced or eliminated in HCC patients at advanced stages of disease. To better activate these cells, we compared the stimulatory capacity of both AFP protein-fed and AdVhAFP-engineered dendritic cells (DC). Healthy donors have CD4 T-cell responses, which were activated in response to AFP protein-fed DC whereas HCC patients do not demonstrate significant responses to AFP protein. AdVhAFP-transduced DC were capable of activating higher frequency TH1 CD4 responses to AFP in both healthy donors and AFP-positive HCC patients. Importantly, CD4 T-cell cytokine expression profiles were skewed towards interleukin-2 and interferon-gamma production when activated by adenovirally engineered DC, which has therapeutic implications for vaccination efforts.
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PMID:AFP-specific CD4+ helper T-cell responses in healthy donors and HCC patients. 1745 17

A preliminary short follow-up study of Hanganutziu and Deicher (HD) antibody titre and sialic acid levels in sera from 7 patients with hepatoma was carried out. Weekly HD antibody titres were abnormal in 6 patients with titres of 4 of the 6 falling to normal in some weeks. Sialic acids levels, however were abnormal (3.830-6.82mmol/ l) compared to those of 33 normal sera (1.08-2.73 mmol/1) throughout the 8 week screening period. There was a poor correlation between the antibody tires and the sialic acid levels (r<0.50) suggesting that at some stage of malignancy, the tumour was expressing N-glycolylneuraminic acid (Neu5Gc), the epitope of HD antigens as well as shedding into circulation, excess N-acetylneuraminic acid (Neu5Gc). Neu5Gc is a tumor-associated antigen. Measurement of antibodies to this epitope have shown that the antibodies have a potential of offering an alternative method of determining tumor growth and/or metastases. A major follow-up study incorporating information on cancer type, disease stage, therapy and the immnunological status of the patient is called for.
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PMID:Serum Hanganutziu and Deicher (HD) antibody and total sialic acid levels in hepatoma patients. 1758 Oct 4

alpha-fetoprotein (AFP) is a fetal protein specifically reexpressed in 50% of hepatocellular carcinomas. This protein could serve as a tumor-associated antigen for immunotherapy purpose. The aim of our work was to analyze the presence of AFP-specific T cell populations in peripheral blood mononuclear cells (PBMCs) from cirrhotic patients with or without hepatocellular carcinoma. Using peptide-major histocompatibility complex class I multimers, AFP-specific populations corresponding to 3 previously described human leukocyte antigen (HLA)-A*0201 major histocompatibility complex class I epitopes (AFP137, AFP158, and AFP325) were sorted magnetically from CD8 positive cells without prior stimulation with the target antigen. T cell populations specific for 1 peptide (AFP158) were frequent, whereas populations corresponding to peptide AFP137 were rare and absent for peptide AFP325. We also isolated and fully characterized T cell clones specific for AFP137 and AFP158 peptides. We show that these clones can be used to monitor dendritic cell loading with peptides and could be useful for future immunotherapy protocols.
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PMID:Detection, isolation, and characterization of alpha-fetoprotein-specific T cell populations and clones using MHC class I multimer magnetic sorting. 1831 63

In vivo studies showed that dendritic cell (DC) dysfunction occurred in tumor microenvironment. As tumors were composed of many kinds of cells, the direct effects of tumor cells on immature DCs (imDCs) are needed for further studies in vitro. In the present study, bone marrow-derived imDCs were incubated with lymphoma, hepatoma and menaloma cells in vitro and surface molecules in imDCs were determined by flow cytometry. Then, imDCs incubated with tumor cells or control imDCs were further pulsed with tumor lysates and then incubated with splenocytes to perform mixed lymphocyte reaction. The DC-dependent tumor antigen-specific T cell proliferation, and IL-12 secretion were determined by flow cytometry, and enzyme-linked immunosorbent assay respectively. Finally, the DC-dependent tumor-associated antigen-specific CTL was determined by enzyme-linked immunospot assay. The results showed that tumor cell-DC incubation down-regulated the surface molecules in imDCs, such as CD80, CD54, CD11b, CD11a and MHC class II molecules. The abilities of DC-dependent antigen-specific T cell proliferation and IL-12 secretion were also decreased by tumor cell incubation in vitro. Most importantly, the ability for antigenic-specific CTL priming of DCs was also decreased by incubation with tumor cells. In the present in vitro study demonstrated that the defective abilities of DCs induced by tumor cell co-incubation and the co-incubation system might be useful for future study of tumor-immune cells direct interaction and for drug screen of immune-modulation.
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PMID:Dysfunction of murine dendritic cells induced by incubation with tumor cells. 1844 43

The expression of alpha-fetoprotein (AFP), a tumor-associated antigen, is silenced in normal adult hepatocyte but reactivated in human hepatocellular carcinoma (HCC). To investigate the roles of AFP in the regulation of cell growth, we silenced AFP expression in the HCC cell line Huh7 by transfection of specific Stealth RNAi. After the transfection for 48 h, the expression of AFP gene was almost abolished, the cell proliferation was inhibited by 46.15%, and the number of cells undergoing early apoptosis was significantly increased to 63.93%. Inhibition of AFP expression also resulted in an increased in Bax/Bcl-2 ratio, the release of cytochrome c from mitochondria and activation of caspase-3. The results suggest that AFP may positively regulate cell proliferation by enhancing the apoptosis resistance via dysfunction of the p53/Bax/cytochrome c/caspase-3 signaling pathway in AFP-producing HCC cell line. As such, the knockdown of AFP gene should be further investigated in vivo as a novel approach to HCC treatment.
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PMID:Silencing alpha-fetoprotein expression induces growth arrest and apoptosis in human hepatocellular cancer cell. 1865 99

Many studies have demonstrated that intracellular proteins, which are involved in carcinogenesis, can provoke autoantibody responses. Therefore, autoantibodies can be used clinically for cancer detection and for proteomic analysis in identification of tumor-associated antigens (TAAs) that are potentially involved in malignant transformation. Liver cancer, especially hepatocellular carcinoma (HCC), is one of the most common tumors in the world. The majority of people with HCC will die within 1 year of its detection. This high case fatality rate can partially be attributed to a lack of diagnostic methods that allow early detection. In the present study, sera from 20 patients with HCC, 30 patients with chronic hepatitis (CH), and 30 patients with liver cirrhosis (LC) as well as sera from 10 normal individuals were used in a proteomic approach to identify HCC-related TAAs. Thirty-four immunoreactive protein spots were excised from the two-dimensional gel electrophoresis (2DE), digested with trypsin, and subsequently analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Of 34 immunoreactive protein spots, 28 were identified. Seventeen of them were not only reactive with serum antibodies in HCC but also with antibodies in pre-HCC conditions, and 11 were only reactive with serum antibodies in HCC but not with antibodies in pre-HCC conditions. In the subsequent analysis, two representative proteins, HSP60 and HSP70, were selected as examples for the validation purpose. The results from immunoassay were consistent with the data from proteomic analysis, supporting our hypothesis that proteins identified with autoantibodies that have been present in precancer conditions may be not appropriate to use as TAA markers in cancer detection.
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PMID:Using proteomic approach to identify tumor-associated antigens as markers in hepatocellular carcinoma. 1867 25

CHP2 (calcineurin B homologous protein 2) was initially identified as a tumor-associated antigen highly expressed in hepatocellular carcinoma. Its biological function remains largely unknown except for a potential role in transmembrane Na(+)/H(+) exchange. In the present study, we observed that ectopic expression of CHP2 promoted the proliferation of HEK293 cells, whereas knockdown of endogenous CHP2 expression in HepG2 inhibited cell proliferation. When inoculated into nude mice, CHP2 transfected HEK293 cells displayed markedly increased oncogenic potential. In analysis of the underlying molecular mechanisms, we found that like calcineurin B, CHP2 was able to bind to and stimulate the phosphatase activity of calcineurin A. In accord with this, CHP2-transfected cells showed increased nuclear presence of NFATc3 (nuclear factor of activated T cells) and enhanced NFAT activity. Finally, both accelerated cell proliferation and NFAT activation following CHP2 transfection could be suppressed by the calcineurin inhibitor cyclosporine A, suggesting an intrinsic connection between these events. Taken together, our results highlighted a potential role of CHP2 in tumorigenesis and revealed a novel function of CHP2 as an activator of the calcineurin/NFAT signaling pathway.
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PMID:CHP2 activates the calcineurin/nuclear factor of activated T cells signaling pathway and enhances the oncogenic potential of HEK293 cells. 1881 28

A glutamine synthetase I family protein, Lengsin, was previously identified as a novel lens-specific transcript in the vertebrate eye. In this report, we show for the first time that Lengsin is a novel tumor-associated antigen expressed ectopically in lung cancer. Interestingly, a novel spliced form of human Lengsin termed 'splicing variant 4', gaining exon 3 that codes extra 63 amino acids, is the dominant transcript form in lung cancer cells. Lengsin mRNA could be detected in 7 of 12 (58%) lung cancer cell lines and 7 of 7 (100%) surgically resected lung cancer tissues. On the other hand, Lengsin transcripts could not be detected in normal major tissues or in other cancer cell lines, including melanoma, colorectal carcinoma, breast carcinoma and hepatocellular carcinoma. In addition, knockdown of Lengsin mRNA with RNAi caused cell death and a decrease of cell viability, suggesting that Lengsin has some essential role in cell survival. Since the lens is an immune-privileged site, we regard Lengsin as a highly immunogenic cancer antigen. Anti-Lengsin autoantibodies were detectable in sera of lung cancer patients, although these patients did not show any lens-related disturbances. Hence, Lengsin splicing variant 4 might be an immunogenic lung cancer-specific antigen that is suitable as a diagnostic marker and for molecular targeting therapy, including immunotherapy.
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PMID:Novel spliced form of a lens protein as a novel lung cancer antigen, Lengsin splicing variant 4. 1945 48

The identification and characterization of tumor-associated antigens (TAAs) and their use in antigen mini-arrays for cancer immunodiagnosis has been of interest recently as an approach to cancer detection. In this study, autoantibodies in sera from a patient with HCC were used as probes to immunoscreen a HepG2 cDNA expression library for the identification of TAAs involved in malignant liver transformation. Recombinant proteins from two genes identified in this manner, Sui1 and RalA were expressed, purified and used as antigens in immunoassays to detect the presence of antibodies in sera from 77 patients with HCC, 30 with chronic hepatitis (CH), 30 with liver cirrhosis (LC) and 82 normal human sera (NHS). The prevalence of antibody to Sui1 and RalA in HCC were 11.7% (9/77) and 19.5% (15/77), respectively, which were significantly higher than prevalence in liver cirrhosis (3.3% and 3.3%), chronic hepatitis (0% and 0%) and normal human sera (0% and 0%). When Sui1 and RalA were added to a panel of eight other TAAs used in a previous study, the final cumulative prevalence of anti-TAA antibodies in HCC to the 10 TAA array was raised to 66.2% (51/77). The specificity for HCC compared with LC, CH and NHS, was 66.7%, 80.0%, and 87.8%, respectively. When anti-TAA was added to abnormal serum AFP as combined diagnostic markers, it raised the diagnostic sensitivity from 66.2% to 88.7%. AFP and anti-TAA were independent markers and the simultaneous use of these two markers significantly resulted in the increased sensitivity of HCC detection.
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PMID:Autoantibodies to tumor-associated antigens combined with abnormal alpha-fetoprotein enhance immunodiagnosis of hepatocellular carcinoma. 1968 63

In order to understand the immunogenicity of a tumor-associated antigen (TAA), Ras family small GTP binding protein (Ra1A) in hepatocellular carcinoma (HCC), autoantibody responses to RalA were evaluated by enzyme-linked immunosorbent assay (ELISA), Western blotting and indirect immunofluorescence assay in sera from patients with HCC and sera from normal individuals. Immunohistochemistry (IHC) study with tissue array slides was also performed to analyze protein expression profiles of RalA in HCC and control tissues. This study demonstrated that RalA had a relative higher frequency of autoantibody response in HCC (20.1%) compared to liver cirrhosis (3.3%), chronic hepatitis (0%), and normal individuals sera (0%). RalA also showed a stepwise increased expression from normal liver tissues (26.7%), liver cirrhosis tissues (45.0%) to HCC tissues (63.3%). Sensitivity and specificity of anti-RalA antibody in detection of HCC was 20.1% and 99.3%, respectively. The data suggested that RalA might contribute to liver malignant transformation, and could be used as a potential tumor marker in HCC detection.
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PMID:Immunogenicity of Ra1A and its tissue-specific expression in hepatocellular carcinoma. 1982 90


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